1,3,4,5-tetrahydropyrrolo(4,3,2-d,e)isoquinolines and related compounds

ABSTRACT

A SERIES OF NOVEL TRICYCLICAZAINDOLE COMPOUNDS HAVE BEEN PREPARED BY CONDENSING THE APPROPRIATE 4-AMINOALKLINDOLE OR A CORRESPONDING 4-AMINOETHOXYINDOLE WITH A SUITABLE ALDEHYDE REAGENT. THE RESULTING TRICYCLIC DERIVATIVES ARE FOUND TO BE USEFUL AS ORAL HYPOGLYCEMIC AGENTS. PREFERRED MEMBER COMPOUNDS INCLUDE 1,3,4,5TETRAHYDRO - - ISOPROPYLPYRROLO 4,3,2, - D,E!ISOQUINOLINE, 3,4,5,6-TETRAHYDRO-3-ISOPROPYL - 8,10 - DIMETHOXY-1H-AZACINO 3,4,5-C,D!INDOLE AND 3,4,5,6-TETRAHYDRO-3-ISOPROPYL-8METHOXY-1H - 1,4 - OXAZOCINO 6,7,8-C,D!INDONE, AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS.

United States Patent O 3,833,591 1,3,4,5TETRAHYDROPYRROLO[4,3,2-d,e]ISO- QUINOLINES AND RELATED COMPOUNDS JamesM. McManus, Old Lyme, Conn., assignor to Pfizer Inc., New York, NY.

N Drawing. Filed Feb. 23, 1972, Ser. No. 228,743 Int. Cl. C07d 57/04 US.Cl. 260-288 R 7 Claims ABSTRACT OF THE DISCLOSURE A series of noveltricyclicazaindole compounds have been prepared by condensing theappropriate 4-aminoalkylindole or a corresponding 4-aminoethoxyindolewith a suitable aldehyde reagent. The resulting tricyclic derivativesare found to be useful as oral hypoglycemic agents. Preferred membercompounds include 1,3,45- tetrahydro 3 isopropylpyrrolo[4,3,2d,e]isoquinoline, 3,4,5,6-tetrahydro-3-isopropyl 8,10dimethoxy-lH-azacino[3,4,5-c,d]indole and3,4,5,6-tetrahydro-3-isopropyl-8- methoxy-lH 1,4oxazocino[6,7,8-c,d]indole, and their pharmaceutically acceptable acidaddition salts.

BACKGROUND OF THE INVENTION This invention relates to new and usefultricyclicazaindole derivatives, which are effective in reducing bloodsugar levels. More particularly, it is concerned with certain novelalkyl and aryl substituted tricyclicazaindoles and theirpharmaceutically acceptable acid addition salts, which are useful asoral hypoglycemic agents for lowering the blood sugar levels of diabeticsubjects.

In the past, various attempts have been made by numerous investigatorsin the field of organic medicinal chemistry to obtain new and usefuloral hypoglycemic agents. For the most part, these efforts haveprincipally involved the synthesis and testing of various new andheretofore unavailable organic compounds, particularly in the area ofthe sulfonylureas. However, in the search for still newer and betteroral hypoglycemic agents, 'very little is known about the activity ofvarious ring-nitrogen compounds like the indoles and their derivatives.For instance, certain aminomethylindole compounds are active, whileothers are not (see U.S. Pat. Nos. 3,459,767 and 3,542,927). On theother hand, several 5,7-dimethoxytryptamines are very active in thisrespect (see US. Pat. No. 3,564,012), but S-methoxy and7-methoxytryptarnines are only useful as analeptic agents (British Pat.Nos. 974,894, 974,893 and 974,895).

SUMMARY OF THE INVENTION In accordance with the present invention, ithas now been rather surprisingly found that certain noveltricyclicazaindole derivatives, i.e., non-sulfonylureas, are extremelyuseful when employed as oral hypoglycemic agents for the treatment ofdiabetic subjects. The novel compounds of this invention are allselected from the group consisting of tricyclicazaindole bases of theformulae:

H i)n-N O NH R1 R3 R1 I R3 J R2 1151: R; H

I II

and the pharmaceutically acceptable acid addition salts thereof, whereinR and R are each a member selected from the group consisting of hydrogenand methoxy, n is an integer of from one to three, inclusive, and R is amember selected from the group consisting of alkyl having from one tosix carbon atoms, cycloalkyl having from three to six carbon atoms,phenylalkyl having up to three carbon atoms in the alkyl moiety, phenyl,chlorophenyl, tolyl, anisyl and thienyl. These compounds are all usefulin lowering blood sugar levels when administered by the oral route ofadministration.

Of especially interest in this connection are the preferred compounds ofthe present invention where R in the aforesaid structural formulae isalkyl having from one to six carbon atoms (and most preferably,isopropyl), or it is cyclohexyl or phenyl. Typical member compounds ofthe preferred class include such tricyclicazaindole compounds as1,3,4,5-tetrahydro-3-isopropyl-pyrrolo- [4,3,2,-d,e]isoquinoline,l,3,4,5-tetrahydro 3 isopropyl- 6,8-dimethoxypyrrolo[4,3,2d,e]isoquinoline, 3,4,5,6-tetrahydro-3-isopropyl-lH-azepino[3,4,5,-c,d]indole, 3,4,5,6- tetrahydro-3-isopr0pyl-8,10- dimethoxylH-azacino [3,4,5- c,d]indole and 3,4,5,6-tetrahydro-3-isopropyl-8-methoxy-1H-1,4-oxazocino [6,7, 8-c,d]indole, and their pharmaceuticallyacceptable acid addition salts such as the hydrochlorides and acetates,respectively. These particular compounds are all highly potent asregards their hypoglycemic activity.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the processemployed for preparing the novel compounds of this invention, anappropriately substituted 4-aminoalkylindole or a corresponding4-aminoethoxyindole is reacted with a suitable aldehyde reagent of theformula R CHO, where R is as previously defined, to form the desiredtricyclicazaindole final product of respectively either formula I or II,as the case may be. This particular reaction is normally conducted in asuitable reaction-inert aprotic organic solvent in the presence of anacid at a temperature that is generally in the range of from about 20 C.up to about C. for a period of about one-half to about 20 hours. Inpractice, it is usually found most convenient to use a slight excess ofthe aldehyde reagent (say, for example, a 10% molar excess of reagent)and to employ an organic acid as catalyst for the reaction. Preferredaprotic solvents for use in the reaction include cyclic ethers such asdioxane and tetrahydrofuran, aromatic hydrocarbon solvents such asbenzene, toluene and Xylene, as well as N,N-dialkyl lower alkanoamideslike N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamideand so on, while preferred organic acids include the lower alkanoicacids such as formic acid, acetic acid, propionic acid, and the like,with glacial acetic acid being most preferred. Upon completion of thereaction, the desired product is readily recovered from the spentreaction mixture by using such conventional means as concentration andcrystallization, etc., or else by first diluting said mixture withwater, followed by basification and subsequent extraction with anorganic solvent to yield the corresponding free base compound per se.

The aforementioned 4-aminoalkylindole starting materials, used in thereaction process of this invention for preparing the compounds offormula I, are either known compounds or else they are easily preparedby those skilled in the art from readily available materials inaccordance with the standard procedures of organic chemistry forpreparing classical amines. For instance, the 4-aminomethylindolecompounds are either known or else readily prepared in two steps fromthe corresponding 4carboxaldehyde, via formation of the intermediateoxime and its subsequent reduction with nascent hydrogen. On the otherhand, the 4-aminoethylindoles are obtained by treating said aldehydewith nitromethane in a condensation reaction and reducing the resultingnitroolefin intermediate with lithium aluminum hydride. Lastly, the4-aminopropylindoles are also obtained from said corresponding aldehydein a series of synthetic organic steps involving (1) a condensationreaction with diethyl malonate (malonic ester) to yield an unsaturateddiester; (2) reduction of said ester via catalytic hydrogenation to givea fully saturated compound that is subsequently hydrolyzed to thecorresponding dibasic acid; (3) decarboxylation of said diacid to thecorresponding monobasic acid and its subsequent conversion to an amide,and '(4) reduction of said amide with lithium aluminum hydride to givethe desired amine. These two last synthetic steps can be brieflyillustrated by the following reaction scheme, where R represents thedesired indole ring moiety, viz.,

The 4-aminoethoxyindole starting materials, on the other hand, used toprepare the compounds of formula II, are all new per se, but are readilyprepared by those skilled in the art starting from easily availablereagents and employing the conventional methods of organic chemistry.For instance, the appropriate 4-hydroxyindole compound can be simplyconverted to the corresponding cyanomethoxy derivative via the use ofchloroacetonitrile and thereafter reduced as such to the desired amineby means of treatment with lithium aluminum hydride, as is hereinafterillustrated by the following reaction scheme where R has the samemeaning as before, viz.,

The pharmaceutically acceptable acid addition salts of thetricyclicazaindole base compounds of this invention (i.e., the finalproducts of formulas I and II) are prepared my simply treating theaforementioned organic bases with various mineral and organic acidswhich form non-toxic acid addition salts having pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate,maleate, fumarate, citrate or acid citrate, tartrate or bitartrate,succinate, gluconate, saccharate, methanesulfonate, ethanesulfonate,benzenesulfonate and p-toluenesulfonate salts. For instance, thesalt-formation step may be carried out using a substantially equimolaramount of the chosen acid in an aqueous solvent medium or in a suitableorganic solvent such as methanol or ethanol. Upon careful evaporation ofthe solvent, the solid salt product is readily obtained.

As previously indicated, the tricyclicazaindole compounds of thisinvention are all readily adapted to therapeutic use as oralhypoglycemic agents, in view of their ability to lower the blood sugarlevels of diabetic and non-diabetic subjects to a statisticallysignificant degree. For instance,1,3,4,5-tetrahydro-3-isopropylpyrrolo[4,3,2- d,e]isoquinoline, a typicaland preferred agent of the present invention, has been found toconsistently lower blood sugar levels in the normal fasted rat to astatistically significant degree when given by the intraperitoneal routeof administration at levels ranging from mg./ kg. to 32 mg./kg.,respectively, without showing any substantial signs of toxic sideeffects. The other compounds of this invention also cause similarresults. Fur thermore, all the herein described compounds of thisinvention can be administered orally, for the present purposes at hand,without causing any significant untoward pharmacological side effects tooccur in the subject to whom they are so administered. In general, thesecompounds are ordinarily administered at dosage levels ranging fromabout 0.4 mg. to about mg. per kg. of body weight per day, althoughvariations will necessarily occur depending upon the weight andcondition of the subject being treated and the particular type of oralformulation chosen.

In connection with the use of the tricyclicazaindole compounds of thisinvention for the treatment of diabetic subjects, it is to be noted thatthey may be administered either alone or in combination withpharameceutically acceptable carriers and that such administration canbe carried out in both single and multiple dosages. More particularly,the novel compounds of the invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically-acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, aqueoussuspensions, elixirs, syrups and the like. Such carriers include soliddiluents or fillers, sterile aqueous media and various non-toxic organicsolvents, etc. Moreover, such oral pharmaceutical compositions can besuitably sweetened and/or flavored by means of various agents of thetype commonly employed for just such a purpose. In general, thetherapeutically-effective compounds of this invention are present insuch dosage forms at concentration levels ranging from about 0.5% toabout by weight of the total composition, i.e., in amounts which aresufficient to provide the desired unit dosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, gelatin and acacia. Additionally, lubricatingagents such as magnesium stearate, sodium lauryl sulfate and talc areoften very useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection would alsoinclude the high molecular weight polyethylene glycols. When aqueoussuspensions and/or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if sodesired, emulsifying and/or suspending agents as well,,together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

The activity of the compounds of the present invention, as hypoglycemicagents, is determined by their ability to lower blood sugar levels inthe normal fasted rat when tested therein for such purposes according tothe procedure described by W. S. Hoffman, as reported in the Journal ofBiological Chemistry, Vol. 120, p. 51 (1937). The latter method measuresdirectly the amount of glucose in the blood at any given time and fromthis, the maximum percent decrease in blood sugar can be readilycalculated and reported as hypoglycemic activity per se. In this way,the present tricyclicazaindole compounds are shown to markedly reducethe blood sugar levels of anesthetized rats when administered to them atdose levels as low as 32 mg./kg. (a dose level at which chlorpropamidefails to elicit a strong response).

aminomethylindole [M. Holbel and V. Liede, Chemise-he Berichte, Vol. 96,p. 1618 (1963)] dissolved in 15 ml. of glacial acetic acid, there wereadded 1.1 g. (0.0154 mole) of isobutyraldehyde in 42 ml. of benzene. Theresulting mixture was then heated in an oil bath at 70 C. for a periodof 1.5 hours, cooled and subsequently treated with 200 ml. of ice andwater. The aqueous layer was separated and made basic with 20% aqueoussodium hydroxide, followed .by extraction of same with diethyl ether.The separated ether layer was then dried over anhydrous magnesiumsulfate, filtered and the dried ethereal filtrate was subsequentlyconcentrated in vacuo to near dryness to afford 1.3 g. of1,3,4,5-tetrahydro-3-isopropylpyrrolo- [4,3,2-d,e]isoquinoline, m.p.177-179 C. After recrystallization from isopropyl ether, the analyticalsample melted at 179-181 C.

,5. AnalysiS.CalCd. for C13H16N2: C, H, N, 13.99. FOUIldI C, 77.86; H,8.04; N, 13.80.

EXAMPLE II The procedure described in Example I was repeated to preparethe following 3-substituted1,3,4,5-tetrahydropyrrolo[4,3,2-d,e]isoquinoline compounds, startingfrom 4- aminomethylindole and the appropriate aldehyde (R CHO) reagentin each case:

1,3,4,5-tetrahydro-3-cyclohexylpyrrolo[4,3,2-d,e]isoquinoline, mp.182-183 C. 1,3,4,5-tetrahydro-3-phenylpyrrolo[4,3,2-d,e]isoquinoline,

mp. 208-210" C. 1,3,4,5-tetrahydro-3-(sec.-butyl)pyrrolo[4,3,2-d,e,]isoquinoline, m.p. 106-108 C. 1,3,4,5-tetrahydro-3-cyclopropylpyrrolo [4,3,2-d,e] isoquinoline, m.p. 208-209 C.

EXAMPLE III To a solution consisting of 66.0 g. (0.37 mole) of5,7-dimethoxyindole [R. Crohare et al., Journal of Heterocyclz'cChemistry, Vol. 7, p. 729 (1970)] dissolved in 350 ml. ofdimethylformamide that was subsequently cooled to C., there were added59.6 g. (0.37 mole) of phosphorus oxychloride in 400 ml. of the samesaid solvent over a period of twenty minutes, while maintaining thetemperature of the reaction mixture at 22-28" C. throughout the courseof the addition. The resulting mixture was then allowed to stir at roomtemperature C.) for a period of one-half hour, followed by the additionof same to a mixture consisting of 6.5 liters of ice and water whichalso contained 148 ml. of 20% aqueous sodium hydroxide. After stirringfor an addition period of 15 minutes, the basified aqueous mixture wasfiltered and the product collected on the filter funnel to give 23.5 g.of 5,7-dimethoxy-4-iudolecarboxaldehyde, m.-p. 164- 170 C. The lattercrystalline material had first been washed with water on the filterfunnel and then air dried to constant weight. Upon recrystallizationfrom benzene, the analytical sample melted at 174-176" C. and possessedthe following absorption characteristics in the ultraviolet region ofthe spectrum, viz.,

at 255 and 345 m (where E=10,781 and 14,750, respectively), With ashoulder at 241 m (E=10,781).

Analysis.Calcd. for C H NO C, 64.39; H, 5.40; N, 6.82. Found: C, 64.68;H, 4.98; N, 6.76.

A solution containing 1.02 g. (0.005 mole) of5,7-dimethoxy-4-indolecarboxaldehyde and 520 mg. (0.007 mole) ofhydroxylamine hydrochloride in 10 ml. of pyridine was allowed to standat room temperature (-25 C.) for a period of 17 hours. The resultingreaction mixture was then poured into 8 ml. of water, and theprecipitated solid product thus obtained was subsequently collected bymeans of suction filtration and air dried to constant weight to afford1.05 g. of 5,7-dimethoxy-4-indolecarboxaldehyde oxime, m.p. 200-204 C.After recrystallization from ethyl acetate, the analytical sample meltedat 206-208" C.

Analysis.-Calcd. for C H N O 1 C, 59.99; H, 5.49; N, 12.72. Found: C,60.01; H, 5.33; N, 12.48.

To a stirred suspension of 4.45 g. (0.02 mole) of 5,7-dimethoxy-indolecarboxaldehyde oxime in 300 ml. of ethanol, there wereadded 29 g. of sodium pellets while the entire system was placed under anitroegn atmosphere. The addition was carried out at such a rate thatthe ethanol solvent system was maintained at the reflux pointthroughout, although some external heat was necessary during the laststages of the addition step in order to completely effect the reaction.

The resulting mixture was then cautiously diluted with 300 ml. of water,and the ethanol was subsequently removed by means of evaporation underreduced pressure to afford 3.65 g. of 4-aminomethyl-5,7-dimethoxyindole6 (mp. 167 C.) in the form of a solid precipitate (initially isolated bymeans of suction filtration and then air dried to constant weight).Recrystallization of the analytical sample first from toluene and thenfrom diethyl ether finally raised the melting point to -173 C.

Analysis.-Calcd. for C H N O C, 64.06; H, 6.84; N, 13.59. Found: C,64.12; H, 7.05; N, 13.18.

To a suspension of 2.6 g. (0.012 mole) of4-aminomethyl-5,7-dimethoxyindole in 28 ml. of benzene containing 1.0 4g. (0.014 mole) of isobutyraldehyde, there were added 1.2 ml. of glacialacetic acid. The resulting mixture was then heated to reflux for aperiod of two hours, followed by cooling in an icebath. The precipitatethus obtained was recovered by means of suction filtration andtriturated in isopropanol to afford 940 mg. of product as the aceticacid addition salt, melting at 199-202 C. The free base compound wasthereafter liberated from the latter acid addition salt, by adding sameto a solution of 20% aqueous sodium hydroxide, followed by extractionwith diethyl ether. Upon drying the ether layer in the usual manner(over anhydrous magnesium sulfate) and subsequently concentrating theresulting filtrate in vacuo, there was obtained pure1,3,4,5-tetrahydro-3-iso-propyl-6,8-dimethoxypyrrolo[4,3,2-d,e]isoquinoline as the residual base. Afterrecrystallization from benzene, the analytical sample melted at 191-194C.

Analysis.-Calcd. for C H N O C, 69.20; H, 7.74; N, 10.76. Found: C,69.44; H, 7.66; N, 10.70.

EXAMPLE IV To 250 ml. of chilled ethanol at 10 C. containing 15.5 g.(0.107 mole) of 4-indolecarboxaldehyde [E. Hardegger and H. Corrodi,Helvetz'ca Chimica Acza, Vol. 37, p. 1826 (1954)] and 16.3 g. (0.267mole) of nitromethane, there were added 15 g. (0.267 mole) of potassiumhydroxide in 65 ml. of water and 130 ml. of ethanol. The resultingsolution was then stirred at 0 C. for a period of 1.5 hours, andthereafter poured into 3 liters of ice and water, followed byacidification with 6N hydrochloric acid. The precipitate which formed atthis point was subsequently collected by means of suction filtration andimmediately added to 100 ml. of acetic anhydride containing 15 g. ofsodium acetate. The resulting reaction mixture was then refluxed for aperiod of ten minutes, followed by removal of the anhydride underreduced pressure. The residue thus obtained Was thereafter treated with200 ml. of water and subsequently made basic by the addition of sodiumcarbonate to afford a gum. Extraction of the latter material withdiethyl ether, followed by drying of the extract and concentration to anoil in the usual manner then gave 5.2 g. of 4-(2'-nitrovinyl)indole,which was immediately used in the next step without any furtherpurification being necessary.

A solution of 6.3 g. (0.166 mole) of 4-(2-nitrovinyl) indole in 100 ml.of tetrahydrofuran was prepared and added dropwise to a slurry of 5.2 g.(0.0276 mole) of lithium aluminum hydride in 100 ml. of the same saidsolvent. The addition step was carried out while the entire system wasplaced under a nitrogen atmosphere. Upon completion of this step, thereaction mixture was allowed to stir for an additional period of 15minutes, followed by the addition of 600 ml. of water and 50 ml. of 20%aqueous sodium hydroxide to the mixture in order to carefully decomposeexcess hydride reagent. The treated aqueous mixture so obtained was thenthoroughly extracted with diethyl ether, and the separated ether layerssubsequently combined and dried over anhydrous sodium sulfate. Afterremoval of the drying agent by means of filtration and the solvent bymeans of evaporation under reduced pressure, there were obtained 2.2 g.of 4- (2'-aminomethyl)indole in the form of a partially solid residue. Aportions of the latter material was then converted to the correspondingpicrate salt for analytical purposes and recrystallized as such fromethyl acetatemethanol to constant melting point. The analytical samplemelted at 243.5 C. (dec.).

Analysis.-Calcd. fOr C H N 'C H N O' 2 C, H, 3.88; N, 17.99. Found: C,49.36 H, 3.90; N, 18.12.

To a solution consisting of 1.2 g. (0.00749 mole) of4-(2'-aminoethyl)indole dissolved in ml. of glacial acetic acid, therewas added 595 mg. (0.00824 mole) of isobutyraldehyde in 25 ml. ofbenzene. The resulting reaction mixture was then heated to 50-55 C. fora period of minutes, cooled and subsequently poured into 150 ml. of iceand water. The aqueous layer was separated and made basic with 20%aqueous sodium hydroxide, followed by extraction of same with diethylether. The separated ether layer was then dried over anhydrous sodiumsulfate, filtered and the dried ethereal filtrate subsequentlyconcentrated in vacuo to afford 590 mg. of 3,4,5,6-tetrahydro 3isopropyl-lH-azepino[3,4,5-c,d] indole (m.p. 171-175 C.) as the residualproduct. After recrystallization from toluene, the analytical samplemelted at 173.5-175" C.

Analysis.Calcd. for C H N C, 78.46; H, 8.46; N, 13.08. Found: C, 78.72;H, 8.29; N, 12.72.

EXAMPLE V A mixture consisting of 4.9 g. (0.024 mole) of 5,7-dimethoxy-4-indolecarboxaldehyde and 1.8 g. (0.024 mole) of ammoniumacetate in 20 ml. of nitromethane was heated on a steam bath for aperiod of 20 minutes. The reaction mixture was then cooled in an icebath, and the precipitate which formed at this point was subsequentlycollected by means of suction filtration. The latter crude product wasslurried in water, filtered again and then air dried to constant weightto aiford 3.26 g. of pure 4-(2-nitrovinyl)-5,7-dimethoxyindole, m.p.159-162 C. After recrystallization from benzene, the analytical samplemelted at 167-169" C.

Analysis.Calcd. for C H N O C, 58.06; H, 4.87; N, 11.29. Found: C,58.23; H, 5.00; N, 11.11.

A solution of 4.2 g. (0.017 mole) of 4-(2'-nitrovinyl)-5,7-dimethoxyindole in 85 ml. of dry tetrahydrofuran was prepared andadded dropwise to a slurry of 3.8 g. (0.102 mole) of lithium aluminumhydride in 70 ml. of the same said solvent, while the entire system wasunder a nitrogen atmosphere. The addition was complete in about onehalfhour. The spent reaction mixture was then cooled to room temperature andthe excess hydride reagent carefully decomposed by the slow additionthereto of 35 m1. of 50% tetrahydrofuran-water (1:1 by volume). Thesolids which formed at this point were then removed by means offiltration, and the resulting filtrate was thereafter concentrated invacuo to provide 3.4 g. of 4-(2'-aminoethyl)- 5,7-dimethoxyindole as theresidual product in the form of a crude oil. A portion of the lattermaterial was then converted to the corresponding picrate salt foranalytical purposes and recrystallized as such from isopropanol to givepure compound. The analytical sample melted at 2l7220 C.

Analysis.-Calcd. for C I-I N O -C H O' C, 48.11; H, 4.26; N, 15.58.Found: C, 48.50; H, 4.28; N, 15.17.

To a stirred suspension of 1.1 g. (0.00499 mole) of4-(2-aminoethyl)-5,7-dimethoxyindole in 10 ml. of henzene containing 2.0ml. of glacial acetic acid, there was added 395 mg. (0.0054 mole) ofisobutyraldehyde dissolved in 10 ml. of benzene. The addition step wascarried out with the aid of some cooling. Upon completion of same, thereaction mixture was allowed to stir at room temperature for a period ofone hour, followed by heating at 50-55 C. for the same period of time.The resulting mixture was then cooled, and the precipitated solidfiltered and air dried to constant weight to give 1.0 g. of 3,4,5,6tetrahydro 3 isopropyl 7,9 dimethoxy 1H- azepino[3,4,5-c,d]indole as theacetate salt, m.p. 189 C. (dec.). After recrystallization fromacetonitrile, the analytical sample melted at 192 C. (dec.).

Analysis.--Calcd. for C16H22N202'C2H402Z C, H, 7.84; N, 8.38. Found: C,64.73; H, 7.82; N, 8.26.

8 EXAMPLE v1 In a flask fitted with a Dean-Stark trap, there was placeda mixture consisting of 20 g. (0.097 mole) of5,7-dimethoxyindole-3-carboxaldehyde, 16.8 g. (0.104 mole) ofdiethylmalonate, 2.0 ml. of pyridine, 2.8 ml. of glacial acetic acid and960 ml. of benzene. The mixture was heated to reflux for a period of 36hours, during which time water was collected in the manner indicatedabove. The benzene solvent was then removed by means of evaporationunder reduced pressure, and the residual material obtained as productwas thereafter triturated with 400 ml. of isopropyl ether to afford 29.2g. of ethyl a-carbethoxy-5,,7-dimethoxyindole-4-acrylate, mp. 107 C.After recrystallization from ethanol-water, the analytical sample meltedat Ill-114 C.

Analysis.Calcd. for C H NO C, 62.23; H, 6.09; N, 4.03. Found: C, 62.38;H, 6.25; N, 4.18.

A mixture of 1.7 g. (0.0049 mole) of ethylu-carbethoxy-5,7-dimethoxyindole-4-acrylate and 350 mg. of platinumoxide in 50 ml. of ethanol was shaken in a hydrogen atmosphere at roomtemperature (-25 C.) and at an initial pressure of 45 p.s.i.g. ofhydrogen. After five hours, the theoretical amount of hydrogen uptakecould be observed. The spent catalyst was then removed from the mixtureby means of suction filtration, and the resulting filtrate thereafterconcentrated in vacuo to afford 1.7 g. of diethyl5,7-dimethoxy-4-indolylmethylmalonate in the form of a brown solidresidue, m.p. 98-102 C. After recrystallization from isopropyl ether,the analytical sample melted at 104-105 C.

Analysis.Calcd. for C H NO C, 61.87; H, 6.64; N, 4.01. Found: C, 61.89;H, 6.67; N, 4.03.

A suspension of 5.6 g. (0.016 mole) of diethyl5,7-dimethoxy-4-indolylmethylmalonate in 34 ml. of 15% aqueous potassiumhydroxide was heated to reflux for a period of one hour. The clearyellow solution which resulted was then cooled in an ice bath and slowlyacidified with 6N hydrochloric acid to give a crystalline precipitate.The latter material was subsequently recovered by means of suctionfiltration and air-dried to constant weight to give a 4.4 g. yield of5,7-dimethoXy-4-indolylmethylmalonic acid, mp. 141-142 C. Afterrecrystallization from ethyl acetate-pentane, the analytical samplemelted at 151 C.

Analysis.Calcd. for C H NO C, 57.33; H, 5.61; N, 4.78. Found: C, 57.14;H, 5.28; N, 4.56.

5,7 Dimethoxy 4 indolylmethylmalonic acid (5.5 g., 0.018 mole) 'waspyrolyzed by a heating bath temperature of 200 C. for a period of tenminutes, while under a reduced pressure of 1.0 mm. Hg. During this time,the solid starting material was observed to melt with a vigorousevolution of gas. Upon completion of this step, the reaction mixture wascooled to room temperature, and the residue subsequently dissolved in 25ml. of 10% (w./ v.) aqueous sodium hydroxide to give a clear solutionimmediately after being filtered. The cooled filtrate was then carefullyacidified with concentrated hydrochloric acid, and the resultingprecipitate subsequently collected by means of suction filtration andair-dried to constant weight to give 3.6 g. of{3-(5,7-dimethoxy-4-indole)propionic acid, m.p. 136-139 C.Recrystallization of the latter material from isopropyl ether thenraised the melting point of the final product to 142144 C.

Analysis.-Calcd. for C13H15NO4: C, H, N, 5.62. Found: C, 62.94; H, 6.22;N, 5.39.

To a chilled solution consisting of 5.0 g. (0.02 mole) of ,8 (5,7dimethoxy-4-indole)propionic acid dissolved in 100 ml. of chloroform at0 C., there were added 2.2 g. (0.022 mole) of triethylamine, followed by2.4 g. (0.022 mole) of ethyl chloroformate. After allowing the reactionmixture to stir at 0 C. for ten minutes, 80 ml. of dimethoxyethane thathad previously been saturated with dry ammonia gas was then addeddropwise to the mixture, with continued stirring being maintainedthroughout the course of the addition step. Upon completion of thisstep, the resulting mixture was stirred in the cold for a period of onehour and then allowed to attain room temperature prior to beingconcentrated in va'cuo. The residual solids obtained in this manner werethen subsequently triturated with 80 ml. of water, and the treatedproduct 'was filtered and air dried to constant weight to give 4.6 g. of8-(5,7-dimethoxy 4 indole)propionamide, m.p. 163-165 C. Afterrecrystallization from toluene, the analytical sample melted at 165l66C.

Analysis.-Calcd. for C H N O C, 62.88; H, 6.50; N, 11.29. Found: C,62.75; H, 6.59; N, 11.06.

A solution of 4.0 g. (0.016 mole) of fi-(5,7-dimethoxy-4-indole)propionamide in 175 ml. of tetrahydrofuran was added dropwise,while under a constant nitrogen atmosphere, to a well-stirred slurryconsisting of 2.3 g. (0.06 mole) of lithium aluminum hydride in 100 ml.of the same said solvent. The addition step was carried out during thecourse of a 15-minute period with agitation of the mixture beingmaintained continuously throughout. Upon completion of this step, thereaction mixture was stirred at room temperature (-25 C.) for a periodof one hour, followed by a period of reflux for 1.5 hours. Water wasthen carefully added to the cooled mixture to decompose excess hydride,and the resulting salts were thereafter removed by means of filtrationto give a clear aqueous filtrate that was subsequently concentrated invacuo. In this manner, there was obtained a 3.4 g. yield of 4-(3-aminopropyl)-5,7-dimethoxyindole as a yellow solid melting at 78-83 C.After recrystallization from isopropyl ether, the pure product melted at9294 C.

Analysis.Calcd. for C H N O C, 66.64; H, 7.74; N, 11.96. Found: C,66.89; H, 7.68; N, 11.72.

A mixture consisting of 2.4 g. (0.01 mole) of 4-(3- aminopropyl) 5,7dimethoxyindole and 790 mg. (0.011 mole) of isobutyraldehyde in 25 ml.of benzene was allowed to stir at room temperature for a period of onehour. The resulting solution was then treated with 2.6 ml. of glacialacetic acid and the reaction mixture was allowed to stir overnight (-16hours) at ambient temperatures. Upon completion of this step, theresulting mixture was refluxed for a period of one hour, then cooled andthereafter treated with 300 ml. of diethyl ether to afford a crystallineprecipitate. The latter material was subsequently recovered by means ofsuction filtration and air dried to constant weight to give 1.8 g. of3,4,5,6-tetrahydro-3-isopropyl 8,10 dimethoxy 1Hazacino[3,4,5-c,d]indole as the acetate salt, m.p. 168169 C. Afterrecrystallization from isopropyl ether, the pure product melted at176-177 C.

Analysis.-Calcd. for C H N O -C H O C, 65.49; H, 8.10; N, 8.04. Found:C, 65.42; H, 7.95; N, 7.69.

Example VII A mixture of 5.3 g. (0.02 mole) of4-benzyloxy-5-methoxyindole [M. Julia et al., Bulletin de al socite'chimique de France, p. 1417 (1965)] and 2.0 g. of 5% palladiumon-carboncatalyst in 50 ml. of ethanol was shaken in a hydrogen atmosphere atroom temperature (-25 C.) and 50 p.s.i.g. of hydrogen (initial pressure)for a period of ten minutes. Upon completion of this step, the catalystwas removed from the mixture by means of filtration and washed on thefilter funnel with some ethanol. The aforesaid washings and filtratewere then combined and subsequently concentrated in vacuo to afford 3.0g. of 4-hydroxy-S-methoxyindole as a crude residual product, m.p. 148152C. After recrystallization from diethyl etherpentane, the analyticalsample melted at 153154 C.

. Analysis.-Calcd. for C H NO C, 66.24; H, 5.56; N,

8.59. Found: C, 66.34; H, 5.60; N, 8.62.

To a well-stirred suspension of 480 mg. of sodium hydrosulfite in 48 ml.of dimethylformamide, there were added 8.0 g. (0.049 mole) of4-hydroxy-S-methoxyindole, followed successively by 2.56 g. (0.053 mole)of 50% sodium hydride and 7.36 g. (0.098 mole) of chloroacetonitrile.The resulting mixture was then allowed to stir at room temperature for aperiod of one hour prior to being treated with 400 ml. of water. Theaqueous mixture so obtained was then carefully extracted with two-250ml. portions of diethyl ether, and the resulting ether extracts werecombined and subsequently concentrated in vacuo to afford an impureresidual oil as product. The latter material was then washed free ofexcess hydride oil with benzene-hexane to give 5.6 g. of4-cyanomethoxy-S-methoxyindole, which was immediately used in the nextreaction step without any further purification being necessary.

A solution consisting of 5.0 g. (0.028 mole) of 4-cyanomethoxy 5methoxyindole in 48 ml. of tetrahydrofuran was prepared and addeddropwise during the course of a 30-minute period to a well-stirredslurry of 2.0 g. (0.056 mole) of lithium aluminum hydride in 40 ml. ofthe same said solvent, while under a dry nitrogen atmosphere at -10 C.The reaction mixture was then allowed to warm to room temperature andthereafter was stirred at that point for a period of one hour. Uponcompletion of this step, the excess hydride reagent was carefullydecomposed by the dropwise addition of 2.0 ml. of water in 10 m1. oftetrahydrofuran to the mixture, followed by the subsequent addition of50 ml. of diethyl ether. The resulting solids obtained in this mannerwere then removed by means of suction filtration and the filtratethereafter concentrated in vacuo to give 5.0 g. of 4-(2-aminoethoxy)-5-methoxyindole in the form of a dark oil. A portion of the lattermaterial was then made to crystallize and after a recrystallization fromisopropyl ether, the product melted at 77-78 C.

Analysis.-Calcd. for C H N O C, 64.06; H, 6.84; N, 13.59. Found: C,63.72; H, 6.65; N, 13.17.

A solution consisting of 2.0 g. (0.01 mole) of 4-(2'- aminoethoxy) 5methoxyindole and 860 mg. (0.012 mole) of isobutyraldehyde in 50 ml. ofbenzene containing 3.0 ml. of glacial acetic acid was heated to 50 C.for a period of 1.5 hours. Upon completion of this step, the resultingmixture was cooled and then concentrated in vacuo to remove the solvent,and the residue was thereafter triturated with diethyl ether to yield2.3 g. of 3,4,5,6- tetrahydro 3 isopropyl 8 methoxy 1H 1,4oxazocino[6,7,8-c,d]indole as the acetate salt, m.p. -171 C.Recrystallization of a portion of the latter material from ethyl acetatethen gave the analytical sample (m.p. 179180 C.).

Analysis.Calcd. for C H N O -C H O C, 63.73; H, 7.55; N, 8.75. Found: C,64.05; H, 7.60; N, 8.49.

EXAMPLE VIII Ten parts of weight of 3,4,5,6-tetrahydro-3-isopropyl-8-methoxy 1H 1,4 oxazocino[6,7,8-c,d]indole acetate in 50 parts by volumeof water is neutralized with 10N aqueous sodium hydroxide solution.Extraction of the resulting aqueous solution with several portions ofmethylene chloride, followed by separation of the organic layer and itssubsequent concentration under reduced pressure then affords3,4,5,6-tetrahydro-3-isopropyl 8 methoxy-1H- 1,4oxazocino[6,7,8-c,d]indole as the free organic base compound.

In like manner, when any of the other tricyclicazaindole salts of thisinvention, like 3,4,5,6 tetrahydro 3 is0 propyl 8,10 dimethoxy 1Hazacino[3,4,5-c,d]indole acetate reported in Example VI, are eachindividually subjected to this very same reaction procedure, thecorresponding free organic base compound is always the final productobtained.

EXAMPLE IX The following tricyclicazaindole compounds are prepared byemploying the appropriate procedures described in the precedingexamples, starting from readily available materials in each instance andusing the proper aldehyde 11 (R CHO) reagent of choice for the finalcondensation step:

SFOCHL..- 100C113 Three--- n-OaHn.

EXAMPLE X CH3. I'l-CaHlS. CycloCaH5.

H B-OCHz -OCH EXAMPLE XI The non-toxic hydrohalide acid addition saltsof each of the tricyclicazaindole base compounds of this inventionreported previously, such as the corresponding hydrochloride,hydrobromide and hydriodide salts, are each individually prepared byfirst dissolving the prespective organic base compound in absolute etherand then adding a saturated solution of the appropriate hydrohalide gasin ethyl acetate to the aforementioned ethereal solution, whereupon thedesired acid addition salt soon precipitates therefrom. In this way, 5.0g. of 1,3,4,5 tetrahydro-3- isopropylpyrrolo[4,3,2-d,e]isoquinoline,obtained as a free base product in Example I, is converted via dryhydrogen chloride gas to the corresponding hydrochloride acid additionsalt in almost quantitative yield.

12 EXAMPLE XII The nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, maleate, fumarate, citrate or acid citrate orbitartrate, succinate, gluconate, saccharate, methanesulfonate,ethanesulfonate, benzenesulfonate and p-toluenesulfonate salts of eachof the aforementioned tricyclicazaindole base compounds reportedpreviously are each prepared by dissolving the proper molar amounts ofthe respective acid and base in separate portions of ethanol and thenmixing the two solutions together, followed by the addition of diethylether to the resultant mixture in order to effect precipitation of thedesired acid addition therefrom. In this manner, equimolar amounts of3,4,5,6 tetrahydro 3 isopropyl 1H azepino[3,4,5- c,d]indole andconcentrated sulfuric acid react to afford the corresponding sulfuricacid addition salt. In like manner, each of the other salt is alsosimilarly prepared.

EXAMPLE XIII A dry solid pharmaceutical composition is prepared byblending the following materials together in the proportions by weightspecified below:

1,3,4,5 Tetrahydro 3 isopropylpyrrolo[4,3,2-d,e]

isoquinoline hydrochloride 50 Sodium citrate 25 Alginic acid 10Polyvinylpyrrolidone 10 Magnesium stearate 5 After the dried compositionis thoroughly blended, tablets are punched from the resulting mixture,each tablet being of such size that it contains mg. of the activeingredient. Other tablets are also prepared in a similar fashioncontaining 5, 10, 25 and 50 mg. of the active ingredient, respectively,by merely using the appropriate amount of the tricyclicazaindole salt ineach case.

EXAMPLE XIV A dry solid pharmaceutical composition is prepared bycombining the following materials together in the proportions by weightindicated below:

3,4,5,6 Tetrahydro 3 isopropyl-8,IO-dimethoxy-IH-azacino[3,4,5-c,d]indole acetate 50 Calcium carbonate 20 Polyethyleneglycol, average molecular weight, 4000- 30 The dried solid mixture soprepared is then thoroughly agitated so as to obtain a powdered productthat is completely uniform in every respect. Soft elastic and hardfilledgelatin capsule containing this pharmaceutical composition are thenprepared, employing a sufiicient quantity of material in each instanceso as to provide each capsule with 250 mg. of the active ingredient.

EXAMPLE XV The tricyclicazaindole final products of Example I, III-IVand VI-VIII were tested for hypoglycemic activity in groups of 8-10 malealbino rats (each weighing 200 g.) of the Sprague-Dawley strain, fastedfor appr0ximately 18-24 hours prior to administration. The rats werefirst lightly anesthetized with pentobarbital (at 15 mg./ kg., i.v.), ablood sample was then taken from the tail vein and the test compound wasadministered intraperitoneally at dose levels of 32, 18 and 10 mg./kg.,respectively. Additional blood samples were then taken at 1, 2 and 4hour intervals after administration of the drug. Blood glucose wasdetermined by adapting the method of W. S. Hoffman [Journal ofBiological Chemistry, Vol. 120, p. 51 (1937)] to the Autoanalyzerinstrument produced by Technicon Instruments Corporation of Chaunce'y,N.Y. On this basis, the maximum percent decrease in blood sugar wascalculated and reported as such (i.e.,

as hypoglycemic activity) for the various compounds listed in the tablebelow:

Hypoglycemlc activity (max. percent fal 1. A compound selected from thegroup consisting of tricyclicazindole bases of the formula R1 Rs 3, andthe pharmaceutically acceptable acid addition salts thereof, wherein Rand R are each a member selected from the group consisting of hydrogenand methoxy and R is a member selected from the group consisting ofalkyl having from one to six carbon atoms, cycloalkyl having from threeto six carbon atoms, phenylalkyl having up to three carbon atoms in thealkyl moiety, phenyl, chlorophenyl, tolyl, anisyl and thienyl.

2. A compound as claimed in Claim 1 wherein R and R are each hydrogenand R is alkyl having from one to six carbon atoms.

3. A compound as claimed in Claim 1 wherein R and R are each methoxy andR is alkyl having from one to six carbon atoms.

4. A compound as claimed in Claim 1 wherein R and R are each hydrogenand R is cycloalkyl having from three to six carbon atoms.

5. A compound as claimed in Claim 1 wherein R and R are each hydrogenand R is phenyl.

6. 1,3,4,5 Tetrahydro 3 isopropylpyrrolo[4,3,2- d,e]isoquinoline.

7. 1,3,4,5 Tetrahydro 3isopropyl-6,8-dimethoxypyrrolo[4,3,2-d,e]isoquinoline.

References Cited UNITED STATES PATENTS 3,330,835 7/1967 Hester 260-288 R3,272,804 9/1966 Archer 260288 R 3,649,634 3/1972 Fujimura 260-288 ROTHER REFERENCES Uyeno in Chem. Abstr., vol. 73, col. 754822 (1970).Chemical Abstracts, vol. 73, Subject Index, p. 3208s (1970).

DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260239 R, 239 B, 376.13 R, 326.15, 326.16; 424244, 258

